Diclofenac sodium, sodium O-(2,6-dichlorophenyl)-acetate is a non-steroidal, anti-inflammatory drug. It is a phenylacetic acid derivative, which was designed based on known structure-activity relationships of other anti-inflammatory drugs. Diclofenac is a weak acid, pKa 4.0. It has a molecular weight of 318.1 and a partition coefficient into n-octanol from aqueous buffer, pH 7.4, of 13:4. Diclofenac can exist as many different salts of which diclofenac sodium is only one.
The chemical structure of diclofenac sodium is as follows: ##STR1##
Diclofenac demonstrates anti-inflammatory, antipyretic, and analgesic activity. It may be unique among non-steroidal, anti-inflammatory drugs in its pharmacological effect on the arachidonic acid cascade. Diclofenac inhibits the cyclooxygenase pathway with subsequent reduction in prostaglandin and thromboxane production. On a molar basis, diclofenac is 3 to 1000 times more potent than other nonsteroidal, anti-inflammatory drugs in inhibiting cyclooxygenase activity. Diclofenac also may inhibit the lipoxygenase pathway with subsequent reduction in leukotriene production. Leukotriene B.sub.4 and other leukotrienes, to a lesser extent, are strong pro-inflammatory compounds. They promote chemotaxis, superoxide production, leukocyte aggregation, and lytic enzyme release. In addition, diclofenac reduces arachidonic acid availability by inhibiting its release and stimulating its reuptake.
The analgesic effect of diclofenac is due primarily to its peripheral action. This may result from diclofenac's inhibition of prostaglandin synthesis. Prostaglandins sensitize pain receptors to mechanical stimulation, and to other chemical mediators including, but not limited to, bradykinin and histamine. The anti-inflammatory effect of diclofenac also may contribute to the drug's analgesic effect. In addition. diclofenac's postulated effect on endorphin release from the pituitary may contribute to its analgesic effects.
Oral diclofenac therapy is associated with marked side effects. Adverse gastrointestinal reactions are the most frequent. The most common gastrointestinal side effects include nausea, vomiting, abdominal pain, dyspepsia and diarrhea. Less frequent side effects include abdominal distension, flatulence and peptic ulcers with bleeding. The incidence of adverse gastrointestinal reactions may approach 30 to 40 percent. These result both from local gastrointestinal irritation and from systemic inhibition of prostaglandin synthesis. Also, there may be an association between oral diclofenac use and hepatic toxicity (Please see Helfgott. S. M.; Snadberg-Cook, J.; Zakim, D. and Nestler, J. Diclofenac-Associated Hepatotoxicity. JAMA, 264; 2660-2662, 1990).
Topical application of diclofenac delivers the drug to the site of inflammation and minimizes diclofenac levels in the gastrointestinal and circulatory systems. Undesirable side effects resulting from oral administration of the drug are greatly reduced and, properly administered in the manner disclosed herein, the topical application produces therapeutic benefits.
Examples of such a topical preparation are found in U.S. Pat. No. 4,543,251 and U.S. Pat. No. 4,670,254 to Kamishita which disclose diclofenac stabilized in a medium comprising water, a lower alkanol, a glycol and a neutralizing agent to which a gelling agent is added. It should be noted that Kamishita does not teach or suggest the use of flux enhancers, moisturizers, or emollients in his gel formulation.
However, the effectiveness of topical diclofenac in treating inflammation and/or painful joints and muscles depends significantly on the particular skin penetrating vehicle with which it is used. To attain effective diclofenac concentrations in a joint's synovial fluid or in a muscle, the gel must have a high transdermal permeation. What is needed is a composition and method for optimizing the transdermal flux of the externally applied diclofenac in order to increase the likelihood of its therapeutic effectiveness.
In addition the vehicle in which topical diclofenac is delivered must by cosmetically acceptable. Because the drug is applied externally, it must be administered periodically due to washing or wearing off. Repeated exposure to alcohol and/or glycol containing gel preparations results in irritation or drying of the skin. Because this is not pleasant, patients tend to stop using the drug, or do not use it according to the proper schedule. When the drug is not applied in the optimal manner, because of the unpleasant delivery system, the condition for which the drug is applied is not optimally treated. What is needed is a topical delivery system that can comfortably used and that will encourage consistent and continuous application needed to achieve optimal and reliable effectiveness.